1. Field of the Invention
The well known narcotic analgesic morphine has the basic ring system: ##STR1## When the oxygen bridge is present and the double bond in the lower ring is removed by saturation, the ring system is referred to as a 4,5.alpha.-epoxy morphinan. When the oxygen bridge is not present, the ring system is referred to as the morphinan system, which has the basic structural formula: ##STR2## in which the numbering of carbon atoms and ring designations are as indicated. When the hydrogen atom attached to the 14-carbon atom is in the .beta.-configuration, i.e., projecting above the plane of the molecule, the molecule has the same B/C ring junction as the naturally occuring morphine alkanoids and is in the B/C cis configuration. When the 14-hydrogen atom is in the .alpha.-configuration, i.e., projecting below the plane of the molecule, it is in the B/C trans configuration.
Morphine and its relatives are used primarily in the relief of pain. They are narcotic and most possess dependence inducing ability and produce other side effects (emesis, constipation, sweating, respiratory depression, miosis) which make them less than ideal analgesics. A compound with an appropriate profile of analgesic (agonist) and narcotic antagonist action has potential as an analgesic free from these side effects. Such a compound would be useful in the treatment of moderate to severe pain, without liability of drug dependence or drug abuse. The search for such an analgesic has led to the synthesis and pharmacological testing of many compounds having the morphinan and 4,5.alpha.-epoxy morphinan nucleus. Among those compounds which have demonstrated interesting agonist/antagonist profiles are morphinans which are methoxy or hydroxy substituted at the 3-position, keto substituted at the 6-position and cycloalkylmethyl substituted at the 17-nitrogen. More recently, it has been discovered that the introduction of a methyl group into the 7-position of a 3-methoxy or hydroxy, 6-keto, 17-cycloalkylmethyl morphinan or 4,5.alpha.-epoxy morphinan can enhance the pharmaceutical utility of such a compound.
The introduction of a methyl group into the 7-position on the morphinan and 4,5.alpha.-epoxy morphinan nucleus has proven difficult and results in only small yields of the desired product. The invention disclosed herein provides a method for the facile introduction of a methyl group, with concurrent 4,5-epoxy bond cleavage, into the 7-position of the morphinan nucleus to thereby provide precursors for therapeutically useful 7-methyl morphinan-6-one compounds.
2. Prior Art
Small et al disclose in U.S. Pat. No. 2,178,010 (issued Oct. 31, 1939) the reaction of dihydrothebaine: ##STR3## with methylmagnesium iodide in refluxing ether solution for 180 hours to give, after workup which includes acid hydrolysis, a mixture from which may be isolated in 45-58% crude yield (15-17.5% recrystallized) methyldihydrothebainone: ##STR4## and a 9-11% yield (5-6% recrystallized) of isomethyl dihydrothebainone: ##STR5##
Small et al. also report in J. Org. Chem., 3, 204 (1938) the reaction of dihydrocodeinone enol acetate: ##STR6## with methylmagnesium iodide for 24 hours in boiling ether to give a 74% yield of IV and some V with no mention of its exact percent yield. It should be noted that the 7-methyl compound V is the mirror product of these reactions and is difficult to obtain. This is in contrast to the presently reported facile introduction of a methyl group, with concurrent 4,5-epoxy bond cleavage, into the 7-position of the morphinan nucleus.
The introduction of a 7-ketone into the morphinan nucleus with concurrent cleavage of the 4,5-epoxy bond has been reported by Rearick and Gates in Tetrahedron Letters, 507 (1970). They report that treatment of 14-bromocodeinone: ##STR7## with Claisens alkali gives the 7-keto morphinane VIII: ##STR8## Sawa et al report the preparation of desoxysinomenine characterized by the formula: ##STR9## and desoxydihydrosinomenine characterized by the formula: ##STR10## in Tetrahedron, 15, 144 (1961).from the naturally occurring alkaloid, sinomenine: ##STR11##
Introduction of 7-substituents on the 4,5-epoxy morphinan nucleus, without cleavage of the epoxy bond has been reported by several workers. Bentley et al report in Chem. Comm., JCS C, 57 (1969) that nitrosyl chloride reacts with thebaine in methanol to give the dimethyl ketal of 7-hydroxyiminoneopinone. Reaction of thebaine with iodine in the presence of AgNO.sub.2 in methanol-chloroform likewise gives the dimethyl ketal of 7.beta.-iodoneopinone.
Lester et al report in Tetrahedron, 20, 1407 (1964) and 21, 771 (1965) that 14-hydroxy-dihydrocodeinone may be converted to the 7-hydroxyimino derivative by reaction with amylnitrite in chloroform containing ethanolic HCl. This compound can be converted to an ethylene ketal and hydrolyzed to the 7-keto-6-ketal which upon further reaction with dimethylsulphoxonium methylide gives the oxirane.